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1.  Sirtuin1 Over-Expression Does Not Impact Retinal Vascular and Neuronal Degeneration in a Mouse Model of Oxygen-Induced Retinopathy 
PLoS ONE  2014;9(1):e85031.
Proliferative retinopathy is a leading cause of blindness, including retinopathy of prematurity (ROP) in children and diabetic retinopathy in adults. Retinopathy is characterized by an initial phase of vessel loss, leading to tissue ischemia and hypoxia, followed by sight threatening pathologic neovascularization in the second phase. Previously we found that Sirtuin1 (Sirt1), a metabolically dependent protein deacetylase, regulates vascular regeneration in a mouse model of oxygen-induced proliferative retinopathy (OIR), as neuronal depletion of Sirt1 in retina worsens retinopathy. In this study we assessed whether over-expression of Sirtuin1 in retinal neurons and vessels achieved by crossing Sirt1 over-expressing flox mice with Nestin-Cre mice or Tie2-Cre mice, respectively, may protect against retinopathy. We found that over-expression of Sirt1 in Nestin expressing retinal neurons does not impact vaso-obliteration or pathologic neovascularization in OIR, nor does it influence neuronal degeneration in OIR. Similarly, increased expression of Sirt1 in Tie2 expressing vascular endothelial cells and monocytes/macrophages does not protect retinal vessels in OIR. In addition to the genetic approaches, dietary supplement with Sirt1 activators, resveratrol or SRT1720, were fed to wild type mice with OIR. Neither treatment showed significant vaso-protective effects in retinopathy. Together these results indicate that although endogenous Sirt1 is important as a stress-induced protector in retinopathy, over-expression of Sirt1 or treatment with small molecule activators at the examined doses do not provide additional protection against retinopathy in mice. Further studies are needed to examine in depth whether increasing levels of Sirt1 may serve as a potential therapeutic approach to treat or prevent retinopathy.
doi:10.1371/journal.pone.0085031
PMCID: PMC3885684  PMID: 24416337
2.  LULL1 Retargets TorsinA to the Nuclear Envelope Revealing an Activity That Is Impaired by the DYT1 Dystonia Mutation 
Molecular Biology of the Cell  2009;20(11):2661-2672.
TorsinA (TorA) is an AAA+ ATPase in the endoplasmic reticulum (ER) lumen that is mutated in early onset DYT1 dystonia. TorA is an essential protein in mice and is thought to function in the nuclear envelope (NE) despite localizing throughout the ER. Here, we report that transient interaction of TorA with the ER membrane protein LULL1 targets TorA to the NE. FRAP and Blue Native PAGE indicate that TorA is a stable, slowly diffusing oligomer in either the absence or presence of LULL1. Increasing LULL1 expression redistributes both wild-type and disease-mutant TorA to the NE, while decreasing LULL1 with shRNAs eliminates intrinsic enrichment of disease-mutant TorA in the NE. When concentrated in the NE, TorA displaces the nuclear membrane proteins Sun2, nesprin-2G, and nesprin-3 while leaving nuclear pores and Sun1 unchanged. Wild-type TorA also induces changes in NE membrane structure. Because SUN proteins interact with nesprins to connect nucleus and cytoskeleton, these effects suggest a new role for TorA in modulating complexes that traverse the NE. Importantly, once concentrated in the NE, disease-mutant TorA displaces Sun2 with reduced efficiency and does not change NE membrane structure. Together, our data suggest that LULL1 regulates the distribution and activity of TorA within the ER and NE lumen and reveal functional defects in the mutant protein responsible for DYT1 dystonia.
doi:10.1091/mbc.E09-01-0094
PMCID: PMC2688546  PMID: 19339278
3.  Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity 
The New England journal of medicine  2011;364(7):603-615.
BACKGROUND
Retinopathy of prematurity is a leading cause of childhood blindness worldwide. Peripheral retinal ablation with conventional (confluent) laser therapy is destructive, causes complications, and does not prevent all vision loss, especially in cases of retinopathy of prematurity affecting zone I of the eye. Case series in which patients were treated with vascular endothelial growth factor inhibitors suggest that these agents may be useful in treating retinopathy of prematurity.
METHODS
We conducted a prospective, controlled, randomized, stratified, multicenter trial to assess intravitreal bevacizumab monotherapy for zone I or zone II posterior stage 3+ (i.e., stage 3 with plus disease) retinopathy of prematurity. Infants were randomly assigned to receive intravitreal bevacizumab (0.625 mg in 0.025 ml of solution) or conventional laser therapy, bilaterally. The primary ocular outcome was recurrence of retinopathy of prematurity in one or both eyes requiring retreatment before 54 weeks’ postmenstrual age.
RESULTS
We enrolled 150 infants (total sample of 300 eyes); 143 infants survived to 54 weeks’ postmenstrual age, and the 7 infants who died were not included in the primary-outcome analyses. Retinopathy of prematurity recurred in 4 infants in the bevacizumab group (6 of 140 eyes [4%]) and 19 infants in the laser-therapy group (32 of 146 eyes [22%], P = 0.002). A significant treatment effect was found for zone I retinopathy of prematurity (P = 0.003) but not for zone II disease (P = 0.27).
CONCLUSIONS
Intravitreal bevacizumab monotherapy, as compared with conventional laser therapy, in infants with stage 3+ retinopathy of prematurity showed a significant benefit for zone I but not zone II disease. Development of peripheral retinal vessels continued after treatment with intravitreal bevacizumab, but conventional laser therapy led to permanent destruction of the peripheral retina. This trial was too small to assess safety.
doi:10.1056/NEJMoa1007374
PMCID: PMC3119530  PMID: 21323540
4.  Retinopathy of prematurity and risk factors: a prospective cohort study 
BMC Pediatrics  2005;5:18.
Background
Increased survival of extremely low birth infants due to advances in antenatal and neonatal care has resulted in a population of infants at high risk of developing retinopathy of prematurity (ROP). Therapeutic interventions include the use of antenatal and postnatal steroids however, their effects on the severity of ROP is in dispute. In addition, it has not been investigated whether severe ROP is due to therapeutic interventions or due to the severity of illness. The aim of the present study was to assess the association between the incidence of severe retinopathy of prematurity (greater than stage 2 – International classification of ROP) and mechanical ventilation, oxygen therapy, gestational age, antenatal and postnatal steroids in extremely low birth weight infants.
Methods
Neonates admitted to the neonatal intensive care unit in Lansing, Michigan, during 1993–2000 were followed to determine factors influencing the development of severe retinopathy of prematurity. Ophthalmologic examinations were started at 6 weeks and followed until resolution. We used logistic regression to estimate the relative risk (odds ratio) associated with risk factors of ROP.
Results
Of the neonates with ≤ 1500 g birth weight, admitted to the neonatal intensive care unit, 85% (616/725) survived. Severe retinopathy of prematurity was detected in 7.8% of 576 neonates who had eye examinations. Neonates of lower gestational age (≤ 25 weeks and 26–28 weeks) had an increased odds ratio of 8.49 and 3.19 for the development of severe retinopathy of prematurity, respectively, compared to those 29 weeks and older. Late postnatal steroid treatment starting after 3 weeks of life showed 2.9-fold increased odds ratio, in particular administration for two weeks and more (OR: 4.09, 95% CI: 1.52–11.03). With increasing antenatal steroids courses the risk of severe retinopathy of prematurity decreased, however, it was not significant. Lower gestational age, dependence on ventilation, and use of postnatal steroids were intertwined. Simultaneous presence of these factors seems to indicate severe disease status.
Conclusion
Prolonged and late postnatal steroids treatment in very low birth weight infants may pose an increased risk for the development of severe retinopathy of prematurity; however, use of postnatal steroids may also be a marker for severity of illness. Further studies need to focus on biologic markers in the pathogenesis of retinopathy of prematurity and to better understand the influence of therapies.
doi:10.1186/1471-2431-5-18
PMCID: PMC1175091  PMID: 15985170
5.  Ophthalmological morbidity in very-low-birthweight infants with bronchopulmonary dysplasia. 
This study was undertaken to determine the relationship between retinopathy of prematurity, ocular sequelae of retinopathy, and bronchopulmonary dysplasia in infants weighing < 1250 g at birth prior to the introduction of steroid therapy for chronic lung disease. Ophthalmological data from 67 infants (22 with severe bronchopulmonary dysplasia and 45 controls) who were enrolled prospectively in an early intervention program were analyzed. The infants had two or more eye examinations prior to discharge and a follow-up examination at 12 to 18 months postconceptual age. The incidence of any retinopathy of prematurity was 33%, and severe retinopathy was 25%. Infants with severe bronchopulmonary dysplasia were 1.7 times more likely to develop any retinopathy and 1.8 times more likely to develop severe retinopathy than controls. The incidence of ocular sequelae, was 45%. Infants with any retinopathy had a 2.3 odds of developing sequelae, and infants with severe retinopathy had a 2.64 odds ratio. When adjusted for bronchopulmonary dysplasia, the odds ratio for developing sequelae was 1.36 in infants with any retinopathy and 1.27 in those with severe retinopathy. The predictors of retinopathy were lower birthweight and gestational age, acidosis, and hypoxemia. Bronchopulmonary dysplasia per se has an adverse effect on ophthalmologic morbidity. Evaluation of the adverse effect of any therapy for chronic lung disease on retinopathy of prematurity should make adjustments for the underlying lung disease.
PMCID: PMC2608256  PMID: 9347682
6.  Evaluating Retinopathy of Prematurity Screening Guidelines for 24-27 Week Gestational Age Infants 
Objective
To determine if current retinopathy of prematurity screening guidelines1 adequately identify treatable ROP in a contemporary cohort of extremely low gestation infants.
Study Design
Data from the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial were used. Inborn infants 24 0/7 to 27 6/7 weeks gestational age with consent prior to delivery were enrolled in 2005-2009. Severe retinopathy of prematurity (Type 1 retinopathy of prematurity or treatment with laser, cryotherapy, or bevacizumab) or death was the primary outcome for the randomized trial. Examinations followed then current American Academy of Pediatrics (AAP) screening recommendations, beginning by 31-33 weeks postmenstrual age.2,3
Results
1316 infants were enrolled in the trial. 997 of the 1121 who survived to first eye exam had final retinopathy of prematurity outcome determined. 137 (14% of 997) met criteria for severe retinopathy of prematurity and 128 (93%) of those had sufficient data (without missing or delayed exams) to determine age of onset of severe retinopathy of prematurity. Postmenstrual age at onset was 32.1 to 53.1 wks. In this referral center cohort, 1.4% (14/997) developed severe retinopathy of prematurity after discharge.
Conclusion
Our contemporary data support the 2013 AAP screening guidelines for ROP for infants 24 0/7 to 27 6/7 weeks gestational age.1 Some infants do not meet treatment criteria until after discharge home. Post-discharge follow-up of infants who are still at risk for severe ROP is crucial for timely detection and treatment.
doi:10.1038/jp.2014.12
PMCID: PMC3969774  PMID: 24503911
extremely premature infant
7.  Photoreceptor Function in School-Aged Children is Affected by Preterm Birth 
Purpose
Prematurely born children have affected visual functions at school age. Optical coherent tomography (OCT) has shown morphological changes in the retina, suggesting a disturbance in normal retinal development in these children. The aim of this study was to examine retinal function with fullfield electroretinogram (ffERG) in school-aged children born prematurely and compare with children born at term. A second aim was to correlate retinal function with visual acuity (VA), gestational age (GA), birth weight, and retinopathy of prematurity (ROP).
Methods
The study group consisted of 35 former preterm children born before GA of 32 weeks. A group of 42 children born at term acted as controls. All children were between 5- and 18-years old. FfERG was performed in both eyes. Best-corrected VA and refraction in cycloplegia was determined.
Results
The a-wave of the combined rod/cone responses was significantly reduced in the prematurely-born children compared with children born at term. There was a correlation between reduced a-wave amplitude in the combined rod/cone response and ROP and GA at birth.
Conclusion
Function of photoreceptors was affected in prematurely born children, possibly also in children without previous ROP. Whether immaturity per se affects the retinal function remains to be elucidated.
Translational Relevance
The present study illustrates that electrophysiological studies of the retinal function can help us understand visual dysfunctions in prematurely born children.
doi:10.1167/tvst.3.6.7
PMCID: PMC4319538
fullfield ERG; prematurity; retinopathy of prematurity
8.  Systematic Review of Digital Imaging Screening Strategies for Retinopathy of Prematurity 
Pediatrics  2008;122(4):825-830.
BACKGROUND
Retinal imaging with remote interpretation could decrease the number of diagnostic eye examinations that premature infants need for the detection of retinopathy of prematurity and thus decrease the time demand on the relatively small pool of ophthalmologists who perform retinopathy of prematurity examinations.
OBJECTIVE
Our goal was to review systematically the evidence regarding the reliability, validity, safety, costs, and benefits of retinal imaging to screen infants who are at risk for retinopathy of prematurity.
METHODS
We searched Medline, the Cochrane library, CINAHL, and the bibliographies of all relevant articles. All English-language studies regardless of design with primary data about our study questions were included. We excluded (1) studies that only included subjects with retinopathy of prematurity, (2) hypothetical models other than cost-effectiveness studies, and (3) validity studies without sufficient data to determine prevalence, sensitivity, and specificity or that only evaluated subjects for 1 component of retinopathy of prematurity (eg, plus disease only).
RESULTS
Studies of only 1 retinal imaging device (RetCam [Clarity Medical Systems, Inc, Pleasanton, CA]) met the inclusion criteria. There was a wide range in reported sensitivity, but specificity was high. There were several important limitations noted, including the eye as the unit of analysis instead of the individual or variations in the criteria for determining a true-positive or true-negative screening result. The risk of retinal hemorrhage resulting from imaging is low, and systemic effects (eg, bradycardia, hypertension, decreased oxygen saturation) are mild. No generalizable cost-effectiveness data were found.
CONCLUSIONS
The evidence base is not sufficient to recommend that retinal imaging be routinely adopted by NICUs to identify infants who have serious retinopathy of prematurity.
doi:10.1542/peds.2007-3667
PMCID: PMC2572706  PMID: 18829807
retinopathy of prematurity; photography; image interpretation; telemedicine; evidence-based medicine; review
9.  Propranolol Inhibition of β-Adrenergic Receptor Does Not Suppress Pathologic Neovascularization in Oxygen-Induced Retinopathy 
Purpose.
Retinopathy of prematurity (ROP) is a leading cause of blindness in children and is, in its most severe form, characterized by uncontrolled growth of vision-threatening pathologic vessels. Propranolol, a nonselective β-adrenergic receptor blocker, was reported to protect against pathologic retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Based on this single animal study using nonstandard evaluation of retinopathy, clinical trials are currently ongoing to evaluate propranolol treatment in stage 2 ROP patients who tend to experience spontaneous disease regression and are at low risk of blindness. Because these ROP patients are vulnerable premature infants who are still in a fragile state of incomplete development, the efficacy of propranolol treatment in retinopathy needs to be evaluated thoroughly in preclinical animal models of retinopathy and potential benefits weighed against potential adverse effects.
Methods.
Retinopathy was induced by exposing neonatal mice to 75% oxygen from postnatal day (P) 7 to P12. Three routes of propranolol treatment were assessed from P12 to P16: oral gavage, intraperitoneal injection, or subcutaneous injection, with doses varying between 2 and 60 mg/kg/day. At P17, retinal flatmounts were stained with isolectin and quantified with a standard protocol to measure vasoobliteration and pathologic neovascularization. Retinal gene expression was analyzed with qRT-PCR using RNA isolated from retinas of control and propranolol-treated pups.
Results.
None of the treatment approaches at any dose of propranolol (up to 60 mg/kg/day) were effective in preventing the development of retinopathy in a mouse model of OIR, evaluated using standard techniques. Propranolol treatment also did not change retinal expression of angiogenic factors including vascular endothelial growth factor.
Conclusions.
Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of β-adrenergic receptors is an appropriate therapeutic approach for treating ROP.
Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of β-adrenergic receptors is an appropriate therapeutic approach for treating ROP.
doi:10.1167/iovs.12-9691
PMCID: PMC3376075  PMID: 22491401
10.  Target Ranges of Oxygen Saturation in Extremely Preterm Infants 
The New England journal of medicine  2010;362(21):1959-1969.
Background
Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes.
Methods
We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant.
Results
The rates of severe retinopathy or death did not differ significantly between the lower-oxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P = 0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P = 0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P<0.001). There were no significant differences in the rates of other adverse events.
Conclusions
A lower target range of oxygenation (85 to 89%), as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors. The increase in mortality is a major concern, since a lower target range of oxygen saturation is increasingly being advocated to prevent retinopathy of prematurity. (ClinicalTrials.gov number, NCT00233324.)
doi:10.1056/NEJMoa0911781
PMCID: PMC2891970  PMID: 20472937
11.  Pain and stress assessment after retinopathy of prematurity screening examination: Indirect ophthalmoscopy versus digital retinal imaging 
BMC Pediatrics  2012;12:132.
Background
Increasingly, neonatal clinics seek to minimize painful experiences and stress for premature infants. Fundoscopy performed with a binocular indirect ophthalmoscope is the reference examination technique for screening of retinopathy of prematurity (ROP), and it is associated with pain and stress. Wide-field digital retinal imaging is a recent technique that should be evaluated for minimizing infant pain and stress.
Methods
The purpose of the study was to assess and compare the impact of using a binocular indirect ophthalmoscope (BIO), or wide-field digital retinal imaging (WFDRI) on pain and stress in infants undergoing ROP screening examination. This was a comparative evaluation study of two screening procedures. Ophthalmologic examinations (N = 70) were performed on 24 infants with both BIO and WFDRI. Pain assessments were performed with two specific neonatal scales (Crying, requires oxygen, increased vital signs, expression and sleeplessness, CRIES and, Premature infant pain profile, PIPP) just prior to the examination, and 30 seconds, 1 hour, and 24 hours later after ending the examination.
Results
Changes over time were significantly different between BIO and WFDRI with both scales (PIPP score, p = .007, and CRIES score, p = .001). Median PIPP score (interquartile interval) at baseline was 4 (3–5). At 30 seconds the score was 8 (6–9) for BIO and 6 (5–7) for WFDRI, respectively. The increase in PIPP score between baseline and 30 seconds was significantly lower with WFDRI (p = .006). The median increase in CRIES score from baseline to 30 seconds was 1 point lower for WFDRI than for BIO (p < .001). No significant difference in response remained at 1 hour or 24 hour assessments.
Conclusions
A transient short-term pain and stress response occurs with both BIO and WFDRI. Infants examined for screening of ROP with digital retinal imaging present less pain and stress at 30 seconds following completion of the exam when compared with binocular indirect ophthalmoscopy.
doi:10.1186/1471-2431-12-132
PMCID: PMC3469398  PMID: 22928523
Diagnostic techniques; Pain measurement; Retinopathy of prematurity; Telemedicine
12.  Alterations in the optic radiations of very preterm children—Perinatal predictors and relationships with visual outcomes☆ 
NeuroImage : Clinical  2013;4:145-153.
Children born very preterm (VPT) are at risk for visual impairments, the main risk factors being retinopathy of prematurity and cerebral white matter injury, however these only partially account for visual impairments in VPT children. This study aimed to compare optic radiation microstructure and volume between VPT and term-born children, and to investigate associations between 1) perinatal variables and optic radiations; 2) optic radiations and visual function in VPT children. We hypothesized that optic radiation microstructure would be altered in VPT children, predicted by neonatal cerebral white matter abnormality and retinopathy of prematurity, and associated with visual impairments.
142 VPT children and 32 controls underwent diffusion-weighted magnetic resonance imaging at 7 years of age. Optic radiations were delineated using constrained spherical deconvolution tractography. Tract volume and average diffusion tensor values for the whole optic radiations and three sub-regions were compared between the VPT and control groups, and correlated with perinatal variables and 7-year visual outcome data.
Total tract volumes and average diffusion values were similar between VPT and control groups. On regional analysis of the optic radiation, mean and radial diffusivity were higher within the middle sub-regions in VPT compared with control children. Neonatal white matter abnormalities and retinopathy of prematurity were associated with optic radiation diffusion values. Lower fractional anisotropy in the anterior sub-regions was associated with poor visual acuity and increased likelihood of other visual defects.
This study presents evidence for microstructural alterations in the optic radiations of VPT children, which are largely predicted by white matter abnormality or severe retinopathy of prematurity, and may partially explain the higher rate of visual impairments in VPT children.
Highlights
•This study compares optic radiations between very preterm and control 7-year-olds.•There are microstructural alterations in the optic radiations of VPT children.•The main risk factors are retinopathy of prematurity and white matter injury.•Microstructural alterations associate with poor visual acuity and visual defects.•This study elucidates neuroanatomical correlates of visual impairment in prematurity.
doi:10.1016/j.nicl.2013.11.007
PMCID: PMC3871291  PMID: 24371797
AD, Axial diffusivity; BWSDS, Birth weight standard deviation score; CI, Confidence interval; CSD, Constrained spherical deconvolution; FA, Fractional anisotropy; GA, Gestational age; MRI, Magnetic resonance imaging; MD, Mean diffusivity; RD, Radial diffusivity; ROP, Retinopathy of prematurity; VPT, Very preterm; Prematurity; Visual system; Tractography; Magnetic resonance imaging; Diffusion weighted imaging
13.  Neurodevelopmental Outcome of Infants With Unilateral or Bilateral Periventricular Hemorrhagic Infarction 
Pediatrics  2009;124(6):e1153-e1160.
OBJECTIVE
Periventricular hemorrhagic infarction (PVHI) is a major contributing factor to poor neurodevelopmental outcomes in preterm infants. We hypothesized that surviving infants with unilateral PVHI would have more favorable outcomes than those with bilateral PVHI.
METHODS
This was a multicenter, retrospective study of infants who were admitted to 3 NICUs in North Carolina from 1998 to 2004. The clinical course and late neuroimaging studies and neurodevelopmental outcomes of 69 infants who weighed <1500 g and had confirmed PVHI on early cranial ultrasonography were reviewed. A predictive model for Bayley Scales of Infant Development, Second Edition, Mental Developmental Index (MDI) <70 was constructed by using radiologic and clinical variables.
RESULTS
Infants with unilateral PVHI had higher median MDI (82 vs 49) and Psychomotor Developmental Index (53 vs 49) than infants with bilateral PVHI. Infants with unilateral PVHI were less likely to have severe cerebral palsy (adjusted odds ratio: 0.15 [95% confidence interval (CI): 0.05–0.45]) than infants with bilateral PVHI. Infants who had unilateral PVHI and developed periventricular leukomalacia and retinopathy of prematurity that required surgery had an increased probability of having MDI <70 compared with those without these complications (probability of MDI <70: 89% [95% CI: 0.64–1.00] vs 11% [95% CI: 0.01–0.28]).
CONCLUSIONS
Infants with unilateral PVHI had better motor and cognitive outcomes than infants with bilateral PVHI. By combining laterality of PVHI, periventricular leukomalacia, and retinopathy of prematurity it is possible to estimate the probability of having an MDI <70, which will assist clinicians when counseling families.
doi:10.1542/peds.2009-0953
PMCID: PMC4000308  PMID: 19948617
ultrasonography; grade 4 intraventricular hemorrhage; preterm infants; outcome
14.  The prevalence and severity of diabetic retinopathy, associated risk factors and vision loss in patients registered with type 2 diabetes in Luganville, Vanuatu 
Aim
To determine the prevalence and severity of diabetic retinopathy in patients with type 2 diabetes in Luganville, the second largest town in Vanuatu. Additionally, to investigate risk factors for retinopathy and the effect of retinopathy on visual acuity (VA) within this group.
Method
All 83 registered patients with type 2 diabetes in Luganville, a town of 13 121 people, were invited for an interview and anthropometric measurements. A questionnaire including assessment of hypertension and glycaemic control, which are known risk factors for diabetic retinopathy, was administered. This sample accounted for approximately 1.07% of Luganville's adult population. Presenting VA was measured. The retina was photographed with a non‐mydriatic fundus camera and images later independently graded for the extent of retinopathy.
Results
68 (82%) of the 83 patients attended. The mean (SD) age was 54 (11) years and 31 (46%) were male. Diabetic retinopathy was present in 36 (52.9%) of the sample. Sight‐threatening retinopathy requiring urgent referral was present in 15 (22.1%) patients. Presenting VA was worse than 6/12 in the better eye in n = 32 (47%) and in up to half of these cases the principal cause was retinopathy. In addition, four people had uniocular blindness resulting from diabetes. The mean body mass index was lower in those patients with diabetes with retinopathy than in those without (p = 0.010), but there were no other significant differences between the two groups and, specifically, no difference in the frequency of retinopathy risk factors. 42 (61.8%) patients had hypertension (⩾135/85 mm Hg) or were taking antihypertensive therapy.
Conclusions
The prevalence of registered patients with diabetes in Luganville's adult population was 1.07%. Diabetic retinopathy was highly prevalent in the sample (in 36, 52.9%), and in 15 (22.1%) there was a significant threat to sight, with up to 25% of the sample possibly already affected by decreased VA or blindness resulting from diabetes‐related eye disease. Retinopathy risk factors were also prevalent. A diabetes screening programme with baseline ophthalmic assessment and follow‐up are urgently needed to enable timely intervention and treatment.
doi:10.1136/bjo.2006.104174
PMCID: PMC1994739  PMID: 17077115
15.  Oral glucose for pain relief during examination for retinopathy of prematurity: a masked randomized clinical trial 
Clinics  2013;68(2):199-203.
OBJECTIVE:
Ophthalmologic examination for retinopathy of prematurity is a painful procedure. Pharmacological and non-pharmacological interventions have been proposed to reduce pain during eye examinations. This study aims to evaluate the analgesic effect of 25% glucose using a validated pain scale during the first eye examination for retinopathy of prematurity in preterm infants with birth weight ≤1,500 g and/or gestational age ≤32 weeks.
METHODS:
A masked, randomized clinical trial for one dose of 1 ml of oral 25% glucose solution 2 minutes before the first ophthalmologic examination for retinopathy of prematurity was conducted between March 2008 and April 2010. The results were compared to those of a control group that did not receive oral glucose solution. Pain was evaluated using a Neonatal Infant Pain Scale immediately before and immediately after the ophthalmologic examination in both groups. Clinicaltrials.gov: NCT00648687
RESULTS:
One hundred and twenty-four patients who were examined for the first time for retinopathy of prematurity were included. Seventy were included in the intervention group and 54 in the control group. The number of patients with pain immediately before the procedure was similar in both groups. The number of patients with pain after ophthalmologic examination was 15.7% in the intervention group and 68.5% in the control group (p<0.001).
CONCLUSIONS:
One ml of oral 25% glucose solution given 2 minutes before an ophthalmologic examination for retinopathy of prematurity was an effective measure for pain relief.
doi:10.6061/clinics/2013(02)OA13
PMCID: PMC3584268  PMID: 23525316
Premature; Retinopathy of Prematurity; Pain; Pain Measurement; Stress; Neonatal Infant Pain Scale (NIPS)
16.  Expression and function of Delta-like ligand 4 in a rat model of retinopathy of prematurity☆ 
Neural Regeneration Research  2013;8(8):723-730.
The Delta-like ligand 4/Notch signaling pathway was shown to participate in the process of retinal development and angiogenesis. However, the function of the Delta-like ligand 4/Notch signaling pathway in retinopathy of prematurity requires further study. Retinopathy of prematurity was induced in 5-day-old Sprague-Dawley rats exposed to hyperoxia for 7 days, and then returned to room air. Reverse transcription-PCR and western blot revealed that Delta-like ligand 4 levels decreased at postnatal day 12 and increased at postnatal day 17 in retinopathy of prematurity rats. Flat-mounted adenosine diphosphatase stained retina and hematoxylin-eosin stained retinal tissue slices showed that the clock hour scores and the nuclei counts in retinopathy of prematurity rats were significantly different compared to normal control rats. After retinopathy of prematurity rats were intravitreally injected with Delta-like ligand 4 monoclonal antibody to inhibit the Delta-like ligand 4/Notch signaling pathway, there was a significant increase in the severity of retinal neovascularization (clock hours) in the intravitreally injected eyes. The nuclei count was highly correlated with the clock hour score. These results suggest that Delta-like ligand 4/Notch signaling plays an essential role in the process of physiological and pathological angiogenesis in the retina.
doi:10.3969/j.issn.1673-5374.2013.08.007
PMCID: PMC4146072  PMID: 25206719
neural regeneration; peripheral nerve injury; Delta-like ligand 4; retinopathy of prematurity; retinal neovascularization; vascular endothelial cells; vascular endothelial growth factor; Notch signaling pathway; oxygen-induced retinopathy; optic nerve disease; photographs-containing paper; neuroregeneration
17.  Clinical factors associated with retinopathy of prematurity. 
Archives of Disease in Childhood  1988;63(5):522-527.
In the period from September 1983 until June 1986 a prospective study was carried out to determine the incidence and severity of retinopathy of prematurity in inborn infants of less than 1500 g at birth and the risk factors associated with the development of retinopathy of prematurity in infants of less than 31 weeks' gestation. One hundred and forty four infants were eligible for inclusion in the study. Altogether 140 infants of less than 1500 g birth weight were examined, 42 (30%) of whom developed retinopathy of prematurity. Fifteen of these infants had progression to advanced disease (stage III or stage IV). One hundred and seventeen of the infants were of less than 31 weeks' gestation and 34 (29%) of them developed retinopathy of prematurity. Thirty four risk factors shown previously to be associated with the development of the disease were collected prospectively and analysed using multiple logistic regression analysis to determine the independently significant variables. Three risk factors: acidosis, the number of times that the pH was less than 7.2; hyperoxia, the number of times that arterial oxygen tension was greater than 12 kPa; and gestational age were found to be independently associated with the development of retinopathy of prematurity in these infants. These findings suggest that acidosis may be an important aetiological factor in the pathogenesis of this disease.
PMCID: PMC1778913  PMID: 3389868
18.  Imaging Retinal Vascular Changes in the Mouse Model of Oxygen-Induced Retinopathy 
Purpose
Oxygen-induced retinopathy in the mouse is the standard experimental model of retinopathy of prematurity. Assessment of the pathology involves in vitro analysis of retinal vaso-obliteration and retinal neovascularization. The authors studied the clinical features of oxygen-induced retinopathy in vivo using topical endoscopy fundus imaging (TEFI), in comparison to standard investigations, and evaluated a system for grading these features.
Methods
Postnatal day (P)7 mice were exposed to 75% oxygen for five days to induce retinopathy or maintained in room air as controls. Retinal vascular competence was graded against standard photographs by three masked graders. Retinal photographs were obtained at predetermined ages using TEFI. Postmortem, retinal vaso-obliteration was measured in whole mounts with labeled vasculature, and retinal neovascularization was quantified in hematoxylin- and eosin-stained ocular cross sections.
Results
Fundus photography by TEFI was possible from P15, when retinal vascular incompetence, including dilatation and tortuosity, was significant in mice with oxygen-induced retinopathy in comparison to controls. Vascular incompetence peaked in severity at P17 and persisted through P25. Comparison with in vitro analyses indicated that vascular changes were most severe after retinal avascularity had begun to decrease in area, and coincident with the maximum of retinal neovascularization. A weighted Fleiss-Cohen kappa indicated good intra- and interobserver agreement for a 5-point grading system.
Conclusions
Topical endoscopy fundus imaging demonstrates retinal vascular incompetence in mice with oxygen-induced retinopathy. The technique complements standard postmortem analysis for following the course of the model.
Translational Relevance
Topical endoscopy fundus imaging has application in the evaluation of novel biologic drugs for retinopathy of prematurity.
doi:10.1167/tvst.1.2.5
PMCID: PMC3763879  PMID: 24049705
retinopathy of prematurity; oxygen-induced retinopathy; retina; imaging
19.  Mitigation of Oxygen-Induced Retinopathy in α2β1 Integrin-Deficient Mice 
Purpose.
The α2β1 integrin plays an important but complex role in angiogenesis and vasculopathies. Published GWAS studies established a correlation between genetic polymorphisms of the α2β1 integrin gene and incidence of diabetic retinopathy. Recent studies indicated that α2-null mice demonstrate superior vascularization in both the wound and diabetic microenvironments. The goal of this study was to determine whether the vasculoprotective effects of α2-integrin deficiency extended to the retina, using the oxygen-induced retinopathy (OIR) model for retinopathy of prematurity (ROP).
Methods.
In the OIR model, wild-type (WT) and α2-null mice were exposed to 75% oxygen for 5 days (postnatal day [P] 7 to P12) and subsequently returned to room air for 6 days (P12–P18). Retinas were collected at postnatal day 7, day 13, and day 18 and examined via hematoxylin and eosin and Lectin staining. Retinas were analyzed for retinal vascular area, neovascularization, VEGF expression, and Müller cell activation. Primary Müller cell cultures from WT and α2-null mice were isolated and analyzed for hypoxia-induced VEGF-A expression.
Results.
In the retina, the α2β1 integrin was minimally expressed in endothelial cells and strongly expressed in activated Müller cells. Isolated α2-null primary Müller cells demonstrated decreased hypoxia-induced VEGF-A expression. In the OIR model, α2-null mice displayed reduced hyperoxia-induced vaso-attenuation, reduced pathological retinal neovascularization, and decreased VEGF expression as compared to WT counterparts.
Conclusions.
Our data suggest that the α2β1 integrin contributes to the pathogenesis of retinopathy. We describe a newly identified role for α2β1 integrin in mediating hypoxia-induced Müller cell VEGF-A production.
In the oxygen-induced retinopathy model of retinopathy of prematurity, α2β1 integrin contributes to the pathogenesis of retinopathy by mediating hypoxia-induced VEGF production by retinal Müller cells.
doi:10.1167/iovs.14-14061
PMCID: PMC4102391  PMID: 24917135
integrin; angiogenesis; retinopathy; Müller cells
20.  Ocular Neovascularization 
Retinal and choroidal vascular diseases constitute the most common causes of moderate and severe vision loss in developed countries. They can be divided into retinal vascular diseases, in which there is leakage and/or neovascularization (NV) from retinal vessels, and subretinal NV, in which new vessels grow into the normally avascular outer retina and subretinal space. The first category of diseases includes diabetic retinopathy, retinal vein occlusions, and retinopathy of prematurity and the second category includes neovascular age-related macular degeneration (AMD), ocular histoplasmosis, pathologic myopia, and other related diseases. Retinal hypoxia is a key feature of the first category of diseases resulting in elevated levels of hypoxia-inducible factor-1 (HIF-1) which stimulates expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor-B (PDGF-B), placental growth factor, stromal-derived growth factor-1 and their receptors as well as other hypoxia-regulated gene products such as angiopoietin-2. Although hypoxia has not been demonstrated as part of the second category of diseases, HIF-1 is elevated and thus the same group of hypoxia-regulated gene products plays a role. Clinical trials have shown that VEGF antagonists provide major benefits for patients with subretinal NV due to AMD and even greater benefits are seen by combining antagonists of VEGF and PDGF-B. It is likely that addition of antagonists of other agents listed above will be tested in the future. Other appealing strategies are to directly target HIF-1 or to use gene transfer to express endogenous or engineered anti-angiogenic proteins. While substantial progress has been made, the future looks even brighter for patients with retinal and choroidal vascular diseases.
doi:10.1007/s00109-013-0993-5
PMCID: PMC3584193  PMID: 23329331
Angiogenesis; age-related macular degeneration; diabetic retinopathy; hypoxia-inducible factor-1; vascular endothelial growth factor; platelet-derived growth factor
21.  Deciphering the Origin of the 2012 Cholera Epidemic in Guinea by Integrating Epidemiological and Molecular Analyses 
Cholera is typically considered endemic in West Africa, especially in the Republic of Guinea. However, a three-year lull period was observed from 2009 to 2011, before a new epidemic struck the country in 2012, which was officially responsible for 7,350 suspected cases and 133 deaths. To determine whether cholera re-emerged from the aquatic environment or was rather imported due to human migration, a comprehensive epidemiological and molecular survey was conducted. A spatiotemporal analysis of the national case databases established Kaback Island, located off the southern coast of Guinea, as the initial focus of the epidemic in early February. According to the field investigations, the index case was found to be a fisherman who had recently arrived from a coastal district of neighboring Sierra Leone, where a cholera outbreak had recently occurred. MLVA-based genotype mapping of 38 clinical Vibrio cholerae O1 El Tor isolates sampled throughout the epidemic demonstrated a progressive genetic diversification of the strains from a single genotype isolated on Kaback Island in February, which correlated with spatial epidemic spread. Whole-genome sequencing characterized this strain as an “atypical” El Tor variant. Furthermore, genome-wide SNP-based phylogeny analysis grouped the Guinean strain into a new clade of the third wave of the seventh pandemic, distinct from previously analyzed African strains and directly related to a Bangladeshi isolate. Overall, these results highly suggest that the Guinean 2012 epidemic was caused by a V. cholerae clone that was likely imported from Sierra Leone by an infected individual. These results indicate the importance of promoting the cross-border identification and surveillance of mobile and vulnerable populations, including fishermen, to prevent, detect and control future epidemics in the region. Comprehensive epidemiological investigations should be expanded to better understand cholera dynamics and improve disease control strategies throughout the African continent.
Author Summary
Cholera is a potentially deadly diarrheic disease caused by the toxin-secreting bacterium Vibrio cholerae. In many poor countries, this prototypical waterborne disease is considered endemic and linked to the climate-driven proliferation of environmental reservoirs of the pathogen. Although such a statement implies radical public health consequences, it has never been proven in Africa. The present study aimed to elucidate the origin of the cholera epidemic that struck the Republic of Guinea in 2012 following a three-year lull period. This investigation integrated a spatiotemporal analysis of the national case databases, field investigations and thorough genetic analyses of 38 clinical bacterial isolates sampled throughout the Guinean epidemic. The Guinean V. cholerae DNA sequence results were aligned and compared with the sequences of nearly 200 strains isolated throughout the world over the past 60 years. Overall, these results suggest that the 2012 cholera epidemic strain was likely imported from Sierra Leone to Guinea by traveling fishermen. The emergence of cholera epidemics due to human-driven activity may be widespread throughout Africa. This highlights the importance of transborder collaborative public health strategies targeting highly mobile and high-risk populations. Similar integrated studies should be conducted in other countries impacted by the disease to better understand the spread of recent epidemics and thus better intercept future outbreaks.
doi:10.1371/journal.pntd.0002898
PMCID: PMC4046952  PMID: 24901522
22.  The AAA+ protein torsinA interacts with a conserved domain present in LAP1 and a novel ER protein 
The Journal of Cell Biology  2005;168(6):855-862.
A glutamic acid deletion (ΔE) in the AAA+ protein torsinA causes DYT1 dystonia. Although the majority of torsinA resides within the endoplasmic reticulum (ER), torsinA binds a substrate in the lumen of the nuclear envelope (NE), and the ΔE mutation enhances this interaction. Using a novel cell-based screen, we identify lamina-associated polypeptide 1 (LAP1) as a torsinA-interacting protein. LAP1 may be a torsinA substrate, as expression of the isolated lumenal domain of LAP1 inhibits the NE localization of “substrate trap” EQ-torsinA and EQ-torsinA coimmunoprecipitates with LAP1 to a greater extent than wild-type torsinA. Furthermore, we identify a novel transmembrane protein, lumenal domain like LAP1 (LULL1), which also appears to interact with torsinA. Interestingly, LULL1 resides in the main ER. Consequently, torsinA interacts directly or indirectly with a novel class of transmembrane proteins that are localized in different subdomains of the ER system, either or both of which may play a role in the pathogenesis of DYT1 dystonia.
doi:10.1083/jcb.200411026
PMCID: PMC2171781  PMID: 15767459
23.  Retinopathy of prematurity: age at onset. 
Archives of Disease in Childhood  1986;61(8):774-778.
The age at which retinopathy of prematurity was first seen was determined in 143 infants. In all, the initial ophthalmological examination was normal. Birth weights varied from 630 to 2700 g and gestational ages from 24.5 to 40.0 weeks. The median postnatal age at which acute retinopathy of prematurity was first seen was 51 and 40 days for those less than 28 and greater than or equal to 28 weeks' gestational age, respectively, and this difference is highly significant. Similar results were obtained when infants were grouped according to birth weight less than 1000 or greater than or equal to 1000 g. Using postmenstrual age as the variable, the first signs of retinopathy of prematurity were seen over a fairly narrow age range and 86% of infants developed retinopathy between 32.5 and 38.5 weeks of age. These findings suggest that the age (but not the occurrence or severity) at which retinopathy of prematurity is first seen is controlled predominantly by stage of development rather than neonatal events.
PMCID: PMC1777954  PMID: 3755580
24.  Genetic susceptibility to retinopathy of prematurity: the evidence from clinical and experimental animal studies 
The British Journal of Ophthalmology  2007;91(12):1704-1708.
Despite advances in management and treatment, retinopathy of prematurity remains a major cause of childhood blindness. Evidence for a genetic basis for susceptibility to retinopathy of prematurity is examined, including the influences of sex, ethnicity, and ocular pigmentation. The role of polymorphisms is explored in the genes for vascular endothelial growth factor and insulin‐like growth factor‐1, and of mutations in the Norrie disease gene. Insights into the genetic basis of retinopathy of prematurity provided by the animal model of oxygen induced retinopathy are examined. Evidence for a genetic component for susceptibility to retinopathy of prematurity is strong, although the molecular identity of the gene or genes involved remains uncertain.
doi:10.1136/bjo.2007.117283
PMCID: PMC2095497  PMID: 18024814
retinopathy of prematurity; oxygen induced retinopathy; angiogenesis; genetic risk factors; molecular genetics
25.  Combination of Intravitreal Ranibizumab and Laser Photocoagulation for Aggressive Posterior Retinopathy of Prematurity 
Case Reports in Ophthalmology  2012;3(1):136-141.
Purpose
To report on 2 cases of aggressive posterior retinopathy of prematurity (ROP) treated with intravitreal ranibizumab (Lucentis®) and laser photocoagulation.
Methods
Two premature females, born at 25 and 26 weeks’ gestation with a birth weight of 530 and 550 g, respectively, with aggressive posterior ROP received combined treatment with laser photocoagulation and intravitreal ranibizumab (0.3 mg [30 µl]) to each eye. Structural outcomes were evaluated by indirect ophthalmoscopy and documented by retinography.
Results
An intravitreal injection was made at 34 weeks of postmenstrual age in the first case, followed by laser photocoagulation 1 week later. There was a partial regression of ROP with treatment. Five weeks later, neovascularization regrowth with bleeding in both eyes (intraretinal and subhyaloid) occurred and retreatment with combined therapy was performed. In the second case, single therapy with laser photocoagulation was made at 34 weeks of postmenstrual age. In spite of the confluent photocoagulation in the avascular area, progression to 4A ROP stage occurred 1 week later. Both eyes were retreated 1 week later with intravitreal ranibizumab and laser photocoagulation. Treatment resulted in ROP regression in both cases. There were no signs of systemic or ocular adverse side effects.
Conclusion
The cases presented show that combination therapy of indirect laser photocoagulation and intravitreal ranibizumab can be effective in the management of aggressive posterior ROP. Further investigation on anti-VEGF safety in premature infants is necessary. Additional studies are needed to define the role of anti-VEGF in ROP treatment.
doi:10.1159/000338623
PMCID: PMC3362187  PMID: 22649347
Retinopathy of prematurity; Laser photocoagulation; Ranibizumab; Anti-VEGF therapy

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